Gene therapy restores immune function in children with rare immunodeficiency
Tuesday, May 11, 2021
Experimental gene therapy can safely restore the immune systems of infants and children with a rare and life-threatening inherited immunodeficiency disorder, according to research supported in part by the National Institutes of Health. The researchers found that 48 of the 50 children who received the gene therapy had retained their restored immune function two to three years later and did not need additional treatments for their disease, known as severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID. The results were published today in the New England Journal of Medicine.
ADA-SCID, which occurs in approximately 1 in 200,000 to 1,000,000 newborns worldwide, is estimated to be caused by mutations in the ADA gene which alters the activity of the enzyme adenosine deaminase necessary for the proper functioning of the immune system. This deficiency leaves children with the disease very susceptible to serious infections. If left untreated, the disease is fatal, usually within the first two years of life.
“These results suggest that this experimental gene therapy could serve as a potential treatment option for infants and older children with ADA-SCID,” said Anthony S. Fauci, MD, director of the National Allergy Institute. and NIH Infectious Diseases (NIAID). “Above all, gene therapy is a unique procedure that offers patients the hope of developing a fully functioning immune system and the chance to live full and healthy lives.”
People with ADA-SCID can be treated with enzyme replacement therapy, but this therapy does not completely restore immune function and should be taken for life, usually once or twice a week. Hematopoietic stem cell transplants, ideally from a genetically matched sibling donor, may provide a more durable solution. However, most people do not have such a donor. In addition, stem cell transplants carry risks such as graft versus host disease and the side effects of chemotherapy drugs given to help donor stem cells establish in the patient’s bone marrow.
The new research evaluated an experimental lentiviral gene therapy designed to be safer and more effective than previously tested gene therapy strategies for ADA-SCID. This gene therapy involves inserting a normal copy of the ADA gene in the patient’s own hematopoietic stem cells. First, stem cells are collected from the patient’s bone marrow or peripheral blood. Then a harmless virus is used as a “vector” or carrier to deliver the normal virus. ADA gene to these cells in the laboratory. The genetically corrected stem cells are then injected back into the patient, who has received a low dose of the chemotherapy drug busulfan to help the cells establish themselves in the bone marrow and start making new immune cells.
Experimental gene therapy, developed by researchers at the University of California, Los Angeles (UCLA) and Great Ormond Street Hospital (GOSH) in London, uses a modified lentivirus to deliver the ADA gene to cells. Previous gene therapy approaches for ADA-SCID relied on a different type of virus called the gamma retrovirus. Some people who received gamma retroviral gene therapy later developed leukemia, which scientists suspect is due to the vector causing the genes that control cell growth to activate. The lentiviral vector is designed to avoid this result and to improve the efficiency of gene delivery into cells.
The results come from three separate Phase 1/2 clinical trials, two conducted in the United States and one in the United Kingdom. The US trials, led by principal investigator Donald Kohn, MD, of UCLA, recruited 30 participants with ADA-SCID aged 4 months to 4 years at UCLA Children’s Hospital Mattel and NIH Clinical Center in Bethesda, Maryland. The UK study, conducted at GOSH and led by lead researcher Claire Booth, MBBS, Ph.D., recruited 20 participants aged 4 months to 16 years. Most of the participants acquired and maintained robust immune function after gene therapy – 96.7% after two years in the US studies and 95% after three years in the UK study – and were able to stop enzyme replacement therapy and other drugs. Of the two participants for whom gene therapy did not restore sustainable immune function, one restarted enzyme replacement therapy and subsequently received a successful stem cell transplant from a donor, and the other restarted therapy. enzyme replacement. Lentiviral gene therapy appeared safe overall, although all participants experienced side effects. Most of them were mild or moderate and due to the chemotherapy the participants received.
The researchers observed similar results in all three trials, although there were some differences between the studies. Stem cells were collected from bone marrow in the US trials and peripheral blood in the UK trial. In one of the US trials, 10 children were treated with genetically corrected stem cells that had been frozen and then thawed. The other two trials used fresh stem cell preparations. In the future, the freezing procedure – known as cryopreservation – could allow stem cells to be more easily transported and processed at a manufacturing facility far from the patient’s home and returned to a local hospital, thereby reducing the burden. need for patients to travel long distances. specialized medical centers to receive gene therapy. A trial of cryopreserved treatment is currently underway at the Zayed Center for Research in Rare Diseases in Children in London, in partnership with GOSH.
For more information on the tests described in the New England Journal of Medicine paper, visit ClinicalTrials.gov under the identifiers NCT01852071, NCT02999984, and NCT01380990. The investigational lentiviral gene therapy, which is licensed to Orchard Therapeutics, has not been approved for use by any regulatory authority.
The research was funded in part by three NIH institutes: NIAID; the National Institute of Heart, Lungs and Blood; and the National Institute for Research on the Human Genome. Additional funding was provided by the California Institute for Regenerative Medicine, the Medical Research Council, the National Institute for Health Research Biomedical Research Center at Great Ormond Street Hospital for Children, the National Health Service Foundation Trust and University College London, and Orchard Therapeutics.
NIAID conducts and supports research – at the NIH, in the United States, and around the world – to study the causes of infectious and immune-mediated diseases and to develop better ways to prevent, diagnose, and treat these diseases. Press releases, fact sheets and other materials related to NIAID are available on the NIAID website.
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DB Kohn, stand C et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. New England Journal of Medicine DOI: 10.1056 / NEJMoa2027675 (2021).